Antifungal T-cell responses of neonates, infants, and children

新生儿、婴儿和儿童的抗真菌 T 细胞反应

• 批准号: 418169051
• 负责人: Professorin Dr. Monika Christine Brunner-Weinzierl
• 金额: --
• 依托单位: Universitätskinderklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418169051?language=en
• 关键词: Antifungal; cell; responses; neonates; infants

Adaptive immune responses of neonates, infants and children react differently than those of adults. Others and we were able to show that in fact CD4 + T cell activation and differentiation is highly age-dependent in early life stages. However, this has so far been demonstrated mainly by antigen-nonspecific polyclonal stimulation. New preliminary results now show that even antigen-specific responses - as a model, antifungal T cell responses to peptides and lysates of the fungi Candida albicans or Aspergillus fumigatus - are vigorously initiated from birth. The neonatologically responsive T cell pool consists of 20 different TCR Vβ families, while pediatric and adult pools show dramatically less variability. We could not show an age-dependent bias for IL-4 expression, but a pronounced IL-17 and IL-10 production. Remarkably, only neonatal and infant T cells showed immediate co-expression of multiple cytokines. In addition, only their naive, activated T cells co-express the transcription factors T-bet and RORγt and subsequently their target genes IL-17 and IFNγ. This indicates that neonatal and infant T cells are predetermined to respond rapidly to high fungal plasticity, which may provide a point of intervention for therapeutic interventions.In the present project, we will focus on functional and molecular aspects of age-related antigen-specific T cell activation and differentiation, using as model our well-characterized antifungal responses to Candida albicans and Aspergillus fumigatus in human T cells. First, we will extend our original work on polyclonal, antigen-unspecific T cell activation to antigen-specific, using MELC technology to analyze the T cell APC synapse. Next, we will identify neonatal-type IL-17 production and its plasticity using kinom profiling, for cytokine signalling, stat analysis, and T-cell differentiation approaches. Another goal is the functional and molecular analysis of antifungal IL-10 producers in neonates, infants, and children, which we see as a key switch to shut down T cell responses (including Th17). Differentiation tests, suppression tests and B-cell helper assays are to be carried out for this purpose. In addition, we will identify signalling pathways that will be initiated for the induction of IL-10 expression in neonatal and pediatric T cells.Together, these experiments provide a comprehensive picture of an antigen-specific T cell response of neonates, infants and children and their signalling pathways in CD4+ T cells. In addition, it will provide insights into the hitherto not understood cellular or molecular causes and age-related differences in fungal infections in humans.

新生儿、婴儿和儿童的适应性免疫反应与成人不同。其他人和我们能够证明，事实上，CD 4 + T细胞的活化和分化在生命早期阶段是高度依赖于年龄的。然而，迄今为止，这主要通过抗原非特异性多克隆刺激来证明。新的初步结果现在表明，即使是抗原特异性反应-作为一个模型，抗真菌T细胞对白色念珠菌或烟曲霉真菌的肽和裂解物的反应-从出生时就开始了。免疫应答性T细胞库由20个不同的TCR Vβ家族组成，而儿童和成人库显示出显著更小的变异性。我们不能显示IL-4表达的年龄依赖性偏倚，但IL-17和IL-10的产生明显。值得注意的是，只有新生儿和婴儿T细胞显示出多种细胞因子的立即共表达。此外，只有其初始活化T细胞共表达转录因子T-bet和RORγt，随后共表达其靶基因IL-17和IFNγ。这表明，新生儿和婴儿的T细胞是预先确定的快速响应高真菌的可塑性，这可能提供了一个点的干预治疗interventions.In本项目中，我们将专注于功能和分子方面的年龄相关的抗原特异性T细胞的激活和分化，使用作为模型，我们的特点，抗真菌反应白色念珠菌和烟曲霉菌在人类T细胞。首先，我们将扩展我们的多克隆，抗原特异性T细胞活化的原始工作，抗原特异性，使用MELC技术来分析T细胞APC突触。接下来，我们将使用kinom分析、细胞因子信号传导、统计分析和T细胞分化方法来鉴定胎盘型IL-17的产生及其可塑性。另一个目标是对新生儿、婴儿和儿童中的抗真菌IL-10产生者进行功能和分子分析，我们认为这是关闭T细胞应答（包括Th 17）的关键开关。为此目的，将进行分化测试、抑制测试和B细胞辅助测定。此外，我们还将确定诱导新生儿和儿科T细胞表达IL-10的信号通路，这些实验为新生儿、婴儿和儿童的抗原特异性T细胞应答及其在CD 4 + T细胞中的信号通路提供了全面的信息。此外，它还将深入了解迄今尚未了解的细胞或分子原因以及人类真菌感染中与年龄相关的差异。